Neurofibrillary tangles (NFTs), a hallmark lesion in Alzheimer's disease (AD), are composed mainly of paired helical filaments (PHF), which have a hyperphosphorylated form of the microtubule associated protein tau as the major component (Nelson et al., “Correlation of Alzheimer's Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature,” JNEN 71:362-381 (2012)). Tau hyperphosphorylation and associated aggregation/oligomerization is thought to be a critical event linked to microtubule disorganization, and the subsequent generation of neurofibrillary tangles which are associated with neuronal toxicity, dysfunction and synaptic loss (Braak et al., “Stages of the Pathologic Process in Alzheimer Disease: Age Categories From 1 to 100 Years,” J Neuropathol. Exp. Neurol 70(11):960-9 (2011)). Oligomeric species of tau are thought to be critical for the “prion-like” spread of pathology and for neuronal toxicity (Guo and Lee, “Cell-to-cell Transmission of Pathogenic Proteins in Neurodegenerative Diseases,” Nat Med 20:130-138 (2014)). Numerous studies have been performed to gain a better understanding of the role of aggregated Aβ species on AD pathology; however, recently there has been much more focus on tau related pathology with the published failure of several amyloid β targeted therapeutic approaches in phase III clinical trials (Drummond and Wisniewski, “Alzheimer's Disease: Experimental Models and Reality,” Acta Neuropathol 133:155-175 (2017)).
The present invention is directed to overcoming these and other deficiencies in the art.